SMC6

SMC6
Identifiers
Aliases	SMC6, SMC-6, SMC6L1, hstructural maintenance of chromosomes 6
External IDs	OMIM: 609387; MGI: 1914491; HomoloGene: 41575; GeneCards: SMC6; OMA:SMC6 - orthologs
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2p24.2 Start 17,663,812 bp[1] End 17,800,242 bp[1]
Gene location (Mouse) Chr. Chromosome 12 (mouse)[2] Band 12|12 A1.1 Start 11,315,887 bp[2] End 11,369,786 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in sperm secondary oocyte Achilles tendon retinal pigment epithelium left testis right testis testicle corpus epididymis Epithelium of choroid plexus ventricular zone Top expressed in tail of embryo genital tubercle primitive streak Rostral migratory stream spermatocyte yolk sac ventricular zone migratory enteric neural crest cell blood spermatid More reference expression data BioGPS More reference expression data
Gene ontology Molecular function nucleotide binding protein binding ATP binding ubiquitin protein ligase binding Cellular component site of double-strand break PML body sex chromosome nuclear speck Smc5-Smc6 complex intracellular anatomical structure nucleoplasm chromosome telomere interchromatin granule nucleus Biological process DNA recombination cellular response to DNA damage stimulus telomere maintenance via recombination cellular senescence positive regulation of chromosome segregation double-strand break repair via homologous recombination DNA repair Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 79677 67241 Ensembl ENSG00000163029 ENSMUSG00000020608 UniProt Q96SB8 Q924W5 RefSeq (mRNA) NM_001142286 NM_024624 NM_025695 NM_001324476 NM_001361252 RefSeq (protein) NP_001135758 NP_078900 NP_001311405 NP_079971 NP_001348181 Location (UCSC) Chr 2: 17.66 – 17.8 Mb Chr 12: 11.32 – 11.37 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Structural maintenance of chromosomes protein 6 is a protein that in humans is encoded by the SMC6 gene.^[5][6]

Structure

The SMC6 was discovered first in fission yeast as RAD18 (SMC6). It forms a heterodimeric complex with Spr18 (SMC5) protein.^[7][8] In yeast, SMC5/6 complex has sub-units which consists of SMC5, SMC6 and six nonstructural maintenance of chromosomes (NSE) proteins. Nse1-Nse3-Nse4 subunits bridge the Smc5 head Smc6 and allow the binding of DNA.^[9][10][11]

It is potentially involved in the Alternative lengthening of telomeres cancer mechanism.^[12]

This depicts the placement of Nse proteins along the SMC5/6 complex in budding and fission yeast. This image does not include Nse2, as its position in the complex is not currently known.

Nse subunits

Nse1-Nse3-Nse4 subunits bridge the heads of the Smc5 and Smc6 proteins and allow the complex to bind DNA. Nse5 and Nse6 form a sub-complex which localizes to the head of the SMC5/6 complex in the budding yeast Saccharomyces cerevisiae, and to the hinges of the SMC5/6 complex in the fission yeast Schizosaccharomyces pombe. The Nse5/6 sub-complex is required for the replication of S. cerevisiae, but has not been characterized as essential in S. pombe. Orthologous proteins to Nse5-Nse6 exist in other eukaryotes, namely ASAP1-SNI1 in Arabidopsis thaliana and SLF1-SLF2 in humans, which are believed have similar function to their Nse counterparts. The localization of SLF1 and SLF2 on the human SMC5/6 complex is unknown.^[13][14]

Localization

The Smc5/6 complex has localization methods which are not heavily conserved. In humans the complex is localized to viral DNA sequences using SMC5/6 localization factors 1 and 2 (SLF1 and SLF2) which contributes to viral resistance.^[15] In the plant A. thaliana, this heterodimer can be localized to double stranded breaks for homologous recombination using the SWI3B complex of the SWI/SNF pathway.^[16] Once localized to the DNA, the SCM5/6 complex non-specifically binds to ~20 DNA base pairs.^[17]

Role in recombination and meiosis

Smc6 and Smc5 proteins form a heterodimeric ring-like structure and together with other non-SMC elements form the SMC-5/6 complex. In the worm Caenorhabditis elegans this complex interacts with the HIM-6(BLM) helicase to promote meiotic recombination intermediate processing and chromosome maturation.^[18] The SMC-5/6 complex in mouse oocytes is essential for the formation of segregation competent bivalents during meiosis.^[19] In the yeast Saccharomyces cerevisiae, SMC6 is necessary for resistance to DNA damage as well as for damage-induced interchromosomal and sister chromatid recombination.^[20] In humans, a chromosome breakage syndrome characterized by severe lung disease in early childhood is associated with a mutation in a component of the SMC-5/6 complex.^[21] Patient’s cells display chromosome rearrangements, micronuclei, sensitivity to DNA damage and defective homologous recombination.

References

1. GRCh38: Ensembl release 89: ENSG00000163029 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000020608 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Wiemann S, Weil B, Wellenreuther R, Gassenhuber J, Glassl S, Ansorge W, Bocher M, Blocker H, Bauersachs S, Blum H, Lauber J, Dusterhoft A, Beyer A, Kohrer K, Strack N, Mewes HW, Ottenwalder B, Obermaier B, Tampe J, Heubner D, Wambutt R, Korn B, Klein M, Poustka A (Mar 2001). "Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs". Genome Res. 11 (3): 422–35. doi:10.1101/gr.GR1547R. PMC 311072. PMID 11230166.
6. "Entrez Gene: SMC6 structural maintenance of chromosomes 6".
7. Fousteri MI, Lehmann AR (April 2000). "A novel SMC protein complex in Schizosaccharomyces pombe contains the Rad18 DNA repair protein". The EMBO Journal. 19 (7): 1691–702. doi:10.1093/emboj/19.7.1691. PMC 310237. PMID 10747036.
8. Lehmann AR, Walicka M, Griffiths DJ, Murray JM, Watts FZ, McCready S, Carr AM (December 1995). "The rad18 gene of Schizosaccharomyces pombe defines a new subgroup of the SMC superfamily involved in DNA repair". Molecular and Cellular Biology. 15 (12): 7067–80. doi:10.1128/mcb.15.12.7067. PMC 230962. PMID 8524274.
9. Palecek J, Vidot S, Feng M, Doherty AJ, Lehmann AR (December 2006). "The Smc5-Smc6 DNA repair complex: bridging of the Smc5-Smc6 heads by the KLEISIN, Nse4, and non-Kleisin subunits". The Journal of Biological Chemistry. 281 (48): 36952–36959. doi:10.1074/jbc.M608004200. PMID 17005570.
10. Zabrady K, Adamus M, Vondrova L, Liao C, Skoupilova H, Novakova M, Jurcisinova L, Alt A, Oliver AW, Lehmann AR, Palecek JJ (February 2016). "Chromatin association of the SMC5/6 complex is dependent on binding of its NSE3 subunit to DNA". Nucleic Acids Research. 44 (3): 1064–1079. doi:10.1093/nar/gkv1021. PMC 4756808. PMID 26446992.
11. Vondrova L, Kolesar P, Adamus M, Nociar M, Oliver AW, Palecek JJ (June 2020). "A role of the Nse4 kleisin and Nse1/Nse3 KITE subunits in the ATPase cycle of SMC5/6". Scientific Reports. 10 (1): 9694. Bibcode:2020NatSR..10.9694V. doi:10.1038/s41598-020-66647-w. PMC 7297730. PMID 32546830.
12. Potts PR, Yu H (2007). "The SMC5/6 complex maintains telomere length in ALT cancer cells through SUMOylation of telomere-binding proteins". Nat. Struct. Mol. Biol. 14 (7): 581–90. doi:10.1038/nsmb1259. PMID 17589526. S2CID 7915836.
13. Yan, Shunping; Wang, Wei; Marqués, Jorge; Mohan, Rajinikanth; Saleh, Abdelaty; Durrant, Wendy E.; Song, Junqi; Dong, Xinnian (2013-11-21). "Salicylic Acid Activates DNA Damage Responses to Potentiate Plant Immunity". Molecular Cell. 52 (4): 602–610. doi:10.1016/j.molcel.2013.09.019. ISSN 1097-2765. PMC 3863363. PMID 24207055.
14. Diaz, Mariana; Pecinka, Ales (2018-01-12). "Scaffolding for Repair: Understanding Molecular Functions of the SMC5/6 Complex". Genes. 9 (1): 36. doi:10.3390/genes9010036. ISSN 2073-4425. PMC 5793187. PMID 29329249.
15. Oravcová, Martina; Nie, Minghua; Zilio, Nicola; Maeda, Shintaro; Jami-Alahmadi, Yasaman; Lazzerini-Denchi, Eros; Wohlschlegel, James A; Ulrich, Helle D; Otomo, Takanori; Boddy, Michael N (2022-11-14). Chiolo, Irene E; Tyler, Jessica K (eds.). "The Nse5/6-like SIMC1-SLF2 complex localizes SMC5/6 to viral replication centers". eLife. 11: e79676. doi:10.7554/eLife.79676. ISSN 2050-084X. PMC 9708086. PMID 36373674.
16. Jiang, Jieming; Mao, Ning; Hu, Huan; Tang, Jiahang; Han, Danlu; Liu, Song; Wu, Qian; Liu, Yiyang; Peng, Changlian; Lai, Jianbin; Yang, Chengwei (2019-07-23). "A SWI/SNF subunit regulates chromosomal dissociation of structural maintenance complex 5 during DNA repair in plant cells". Proceedings of the National Academy of Sciences. 116 (30): 15288–15296. Bibcode:2019PNAS..11615288J. doi:10.1073/pnas.1900308116. ISSN 0027-8424. PMC 6660752. PMID 31285327.
17. Yu, You; Li, Shibai; Ser, Zheng; Kuang, Huihui; Than, Thane; Guan, Danying; Zhao, Xiaolan; Patel, Dinshaw J. (2022-06-07). "Cryo-EM structure of DNA-bound Smc5/6 reveals DNA clamping enabled by multi-subunit conformational changes". Proceedings of the National Academy of Sciences. 119 (23): e2202799119. Bibcode:2022PNAS..11902799Y. doi:10.1073/pnas.2202799119. ISSN 0027-8424. PMC 9191643. PMID 35648833.
18. Hong Y, Sonneville R, Agostinho A, Meier B, Wang B, Blow JJ, Gartner A (2016). "The SMC-5/6 Complex and the HIM-6 (BLM) Helicase Synergistically Promote Meiotic Recombination Intermediate Processing and Chromosome Maturation during Caenorhabditis elegans Meiosis". PLOS Genet. 12 (3): e1005872. doi:10.1371/journal.pgen.1005872. PMC 4807058. PMID 27010650.
19. Hwang G, Sun F, O'Brien M, Eppig JJ, Handel MA, Jordan PW (2017). "SMC5/6 is required for the formation of segregation-competent bivalent chromosomes during meiosis I in mouse oocytes". Development. 144 (9): 1648–1660. doi:10.1242/dev.145607. PMC 5450844. PMID 28302748.
20. Onoda F, Takeda M, Seki M, Maeda D, Tajima J, Ui A, Yagi H, Enomoto T (2004). "SMC6 is required for MMS-induced interchromosomal and sister chromatid recombinations in Saccharomyces cerevisiae". DNA Repair (Amst.). 3 (4): 429–39. doi:10.1016/j.dnarep.2003.12.007. PMID 15010319.
21. van der Crabben SN, Hennus MP, McGregor GA, Ritter DI, Nagamani SC, Wells OS, Harakalova M, Chinn IK, Alt A, Vondrova L, Hochstenbach R, van Montfrans JM, Terheggen-Lagro SW, van Lieshout S, van Roosmalen MJ, Renkens I, Duran K, Nijman IJ, Kloosterman WP, Hennekam E, Orange JS, van Hasselt PM, Wheeler DA, Palecek JJ, Lehmann AR, Oliver AW, Pearl LH, Plon SE, Murray JM, van Haaften G (2016). "Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease". J. Clin. Invest. 126 (8): 2881–92. doi:10.1172/JCI82890. PMC 4966312. PMID 27427983.

Further reading

• Hartley JL, Temple GF, Brasch MA (2001). "DNA cloning using in vitro site-specific recombination". Genome Res. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
• Simpson JC, Wellenreuther R, Poustka A, et al. (2001). "Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing". EMBO Rep. 1 (3): 287–92. doi:10.1093/embo-reports/kvd058. PMC 1083732. PMID 11256614.
• Taylor EM, Moghraby JS, Lees JH, et al. (2001). "Characterization of a novel human SMC heterodimer homologous to the Schizosaccharomyces pombe Rad18/Spr18 complex". Mol. Biol. Cell. 12 (6): 1583–94. doi:10.1091/mbc.12.6.1583. PMC 37326. PMID 11408570.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
• Wiemann S, Arlt D, Huber W, et al. (2004). "From ORFeome to biology: a functional genomics pipeline". Genome Res. 14 (10B): 2136–44. doi:10.1101/gr.2576704. PMC 528930. PMID 15489336.
• Hillier LW, Graves TA, Fulton RS, et al. (2005). "Generation and annotation of the DNA sequences of human chromosomes 2 and 4". Nature. 434 (7034): 724–31. Bibcode:2005Natur.434..724H. doi:10.1038/nature03466. PMID 15815621.
• Potts PR, Yu H (2005). "Human MMS21/NSE2 is a SUMO ligase required for DNA repair". Mol. Cell. Biol. 25 (16): 7021–32. doi:10.1128/MCB.25.16.7021-7032.2005. PMC 1190242. PMID 16055714.
• Mehrle A, Rosenfelder H, Schupp I, et al. (2006). "The LIFEdb database in 2006". Nucleic Acids Res. 34 (Database issue): D415–8. doi:10.1093/nar/gkj139. PMC 1347501. PMID 16381901.
• Potts PR, Porteus MH, Yu H (2006). "Human SMC5/6 complex promotes sister chromatid homologous recombination by recruiting the SMC1/3 cohesin complex to double-strand breaks". EMBO J. 25 (14): 3377–88. doi:10.1038/sj.emboj.7601218. PMC 1523187. PMID 16810316.